T cell mediated immune responses are initiated through antigen recognition by the T cell receptor (TCR). The ultimate amplitude and quality of the T cell response is regulated by immune checkpoints, which control the balance of co-stimulatory and co-inhibitory signals. Immune checkpoints are essential in maintaining self-tolerance and protecting tissues from damage during immune response to infection. However, dysregulated expression of immune checkpoint proteins by tumors provides an important immune resistance mechanism. Inhibitory ligands and receptors that regulate T cell effector functions in tissues are frequently overexpressed on tumor cells or on non-transformed cells in the tumor microenvironment. Two general mechanisms of expression of immune checkpoint ligands on tumor cells have emerged. In some tumors, constitutive oncogenic signaling induces inhibitor ligand expression on the tumor to provide innate immune resistance. Alternatively, an inhibitory ligand may be induced in response to inflammatory signals that are produced by an active anti-tumor immune response (adaptive immune resistance). Pre-clinical and clinical data indicates that inhibition of immune checkpoints can enhance endogenous anti-tumor immunity (see, e.g., Pardoll, Nat. Rev. Cancer 12:252, 2012).
There is a need in the art for alternative, effective modulators of immune checkpoint pathways. The present disclosure meets such needs, and further provides other related advantages.